Antibiotics and human phagocytic cells
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1. The first studies of this thesis concerned human phagocytic cells in vivo as they responded to physical trauma in an experimental skin abrasion. This showed the sequence of cellular responses during acute inflammation and provided quantitative data about the phagocytic cell concentrations at each stage. 2. In an identical skin abrasion several antibiotics, administered systemically, were assayed. This provided information about the approximate concentration of each drug in acute inflammatory exudates. 3. A series of in vitro tests were performed to quantify the rate at which phagocytic cells, or the various antibiotics, could inactivate Staphylococcus aureus type 42b. The concentrations used were based on concentrations measured in vivo (paragraphs 1 and 2 above). These studies showed that phagocytosis by human granulocytes is rapid (T-§- = 5.6 minutes), but subsequent intracellular killing is much slower. In a cell-free system different antibiotics had variable rates of bacterial inactivation but, in general, these rates were of the same order as the rate of intracellular killing by normal/ normal human granulocytes. All these experiments utilised phagocytic cells and antibiotics separately. 4. The most important findings relate to the combined action of phagocytic cells and antibiotics (particularly ampicillin). The first clinical studies showed that during antibiotic therapy the rate of intracellular killing usually decreased. This effect could not be demonstrated by adding ampicillin in vitro to granulocytes during their phase of intracellular killing. However, when ampicillin was administered orally to 4 healthy subjects there was a decrease of intracellular killing at 1 and 2 hours. The exact cause has not been established, but collaborative work indicates that this may be the result of inhibition by ampicillin of leucocyte myeloperoxidase and interference with other enzymes involved in the production or breakdown of intravacuolar hydrogen peroxide. 5. The importance of these findings is discussed in the light of a growing awareness that antibiotic therapy has considerable limitations and may have serious adverse effects.